The major objectives of this proposal are: to assess the nature of the severe insulin resistance seen in association with acanthosis nigricans and/or hyperandrogenemia; to determine the relationship of the three components of this syndrome to one another; and to develop a rational therapeutic approach to the syndrome based on a better understanding of the pathophysiology involved. Glucose and insulin responses tgo an oral glucose challenge, acute glucose reponse to an intravenous insulin bolus, and generation of a biologic insulin dose response curve via the euglycemic clamp technique will provide a detailed in vivo assessment of insulin action. In vivo results will be compared with a detailed in vitro analysis of insulin binding to freshly isolated cells (monocytes, adipocytes), insulin receptor autophosphorylation, and basal and insulin stimulated glucose transport in human adipocytes. Potential intrinsic defects in insulin action will be assessed through family studies and by analysis of receptor and post receptor function (glucose oxidation and transport) in cultured fibroblasts obtained from these subjects. The relationship of insulin resistance, acanthosis nigricans, and hyperandrogenemia will be assessed in the basal state and following sequential therapeutic intervention with diet, a sulfonylurea agent, and an oral contraceptive. The systematic approach as outlined in these affected individuals, combined with similar studies in appropriate weight matched subjects, as well as subjects with evidence of hyperandrogenemia without acanthosis nigricans should allow the accomplishment of the objectives. A clearer understanding of the exact nature of the defects in insulin action in this syndrome and its relation to the other associated components should provide a more rational therapeutic approach not only to this syndrome but other more common disease states as well.